Streptococcus gordonii‐associated infective endocarditis: Case series, literature review, and genetic study

Key Clinical Message Streptococcus gordonii‐associated endocarditis is a rare occurrence, raising diagnostic challenges, and is often associated with considerable morbidity. However, vigilance can prevent devastating consequences. Abstract Streptococcus gordonii‐associated endocarditis is rarely reported but often associated with considerable morbidity. We describe three cases of infective endocarditis caused by S. gordonii during a four‐week period in 2023, and the use of whole‐genome sequencing to determine whether these isolates were genetically related. The available literature was reviewed.


| INTRODUCTION
Streptococcus gordonii is a gram-positive, alpha-hemolytic streptococci that belongs to the viridans group streptococci (VGS). 1 S. gordonii is part of the commensal microbiota in different body locations, including the oral cavity where it is deemed beneficial for maintaining oral health by modulating biofilm formation through competing with other VGS species implicated in dental caries such as Streptococcus mutans. 2,35][6] Although infective endocarditis(IE) caused by S. gordonii has seldom been reported, the clinical presentation seems to be indistinguishable from that caused by other VGS. 7. gordonii IE characteristically presents as a subacute infection, which is often complicated with subsequent valve destruction and emboli formation if not promptly recognized and treated. 8As in IE caused by other VGS species, penicillin remains the first-line antibiotic treatment, which should be coupled with timely surgical intervention if indicated. 9erein, we report a case series of S. gordonii-associated endocarditis with different clinical courses and complications.In addition, whole-genome sequencing (WGS) analysis was performed to determine the possible genetic relatedness among these S. gordonii isolates.Also, we reviewed the literature for similar cases.

| METHODOLOGY
2.1 | Cases description 2.1.1 | Case (1) A 49-year-old man was admitted to the hospital on May 8, 2023 with acute-onset right-sided weakness and global aphasia (3 h duration).Further history revealed fever and night sweats for 1 week and no other symptoms.His medical history is significant for uncontrolled diabetes mellitus and hypertension for the last 5 years.His physical examination revealed a blood pressure (BP) of 108/66 mmHg, a temperature of 38.5°C, a regular pulse rate of 92 beats per minute, a 3/6 holosystolic murmur at the apex, and rightside hemiplegia.Laboratory tests were within normal limits except for a CRP level of 53 mg/L (0-5), and HbA1c of 9.5% (<5.7).The computed tomography of the brain revealed a large area of ischaemia in the left middle cerebral artery territory with a central core infarct.Thrombolysis was complicated by a left basal ganglia haemorrhagic transformation.
A S. gordonii was isolated from 2 sets of blood cultures (3/4 bottles, from different venipuncture sites), which was susceptible to penicillin (MIC 0.016).A large vegetation (13 × 8 mm) with abscess formation on the mitral valve was seen on the trans-esophageal echocardiography (TEE) with leaflet perforation, mitral valve regurgitation and a normal ejection fraction of 67% (Figure 1A).He was commenced on ceftriaxone 2 g IV every 24 h, and surgery was deemed to be a high risk given the large haemorrhagic stroke transformation.Two weeks into the therapy, the fever subsided, and a follow-up trans-thoracic echocardiography (TTE) showed a decrease in the size of the abscess and vegetation.Retrospectively, there was no history of dental procedure and no abnormalities on oral examination.He finished 6 weeks of ceftriaxone with a significant resolution of the vegetation and the abscess on the repeated TTE (Figure 1B).

| Case (2)
A 52-year-old man with no significant past medical history presented on May 11, 2023 with fever and fatigue for 8 weeks.His physical examination revealed a BP of 95/51 mmHg, a pulse rate of 58 beats per minute, and a fever (39.2°C) with a pan-systolic murmur at the apex.His blood cultures (One set) revealed a penicillin-susceptible S. gordonii (MIC 0.016), and a TEE showed vegetation on the mitral valve (3 cm), causing leaflet perforation and abscess formation with ejection fraction of 59% (Figure 2).He was treated with a 4-week course of ceftriaxone 2 g IV every 24 h and underwent mitral valve replacement, and ceftriaxone was continued for 4 weeks.There was no history of dental procedures identified, and the patient recovered fully and was discharged home.He remained asymptomatic at the 6-week follow-up appointment.

| Case (3)
A 19-year-old man presented on June 5, 2023 with fever and unintentional weight loss associated with night sweats for 3 months.He had been on iron replacement therapy for the last 4 months due to his iron deficiency anemia.His physical examination revealed a BP of 96/56 mmHg, a pulse rate of 73 beats per minute, a fever of 38.1°C and hepatosplenomegaly.The cardiac examination revealed a faint systolic murmur in the aortic area.Two blood culture sets (4/4 bottles) grew a penicillin-susceptible S. gordonii (MIC 0.094).A TTE revealed no evidence of vegetations and normal ejection fraction; however, a TEE showed severe aortic valve regurgitation with vegetation (10 × 3 mm) and intra-valvular non-ruptured abscess formation (Figure 3).Urgent aortic valve replacement was performed successfully, and he recovered fully after completing 4 weeks of treatment with ceftriaxone (2 g IV every 24 h).He traveled back to his country and was lost to follow-up.

| Microbiological identification and antimicrobial susceptibility testing
Microbiological identification and antimicrobial susceptibility tests (AST) were performed using matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS), Bruker Daltonics MALDI Biotyper (Billerica, MA, USA) and BD Phoenix TM system using the NMIC/ID-94 panel according to manufacturer's instructions.
The isolates were identified as S. gordonii (log scores of 2.34, 2.16, and 2.14 respectively).The antibiotic susceptibility was performed as recommended by CLSI and all three isolates were susceptible to penicillin (MIC ≤0.12 μg/mL).
The genome size of S. gordonii is around 2.2 Mb, and genomic analysis were performed to determine the relationship between these 3 isolates.The core genome SNPs revealed that these 3 isolates were not similar but with >60,000 SNPs differences among them despite the occurrence within a month from two hospitals (Figure 4).Both 25,148 and 28,379 carried tet(M) that confers resistance to tetracycline and doxycycline.The genome of 28,379 also carries msr(D) and mef(A) that are responsible for resistance towards azithromycin, erythromycin, and telithromycin.The three isolates shared similar pathogenicity genes profile, including cell surface hydrophobicity proteins such as cshA and cshB, the adherence and the colonization genes including pavA, srtA, slrA, plr/gapA, gtfG and lmb, evasion from the immune system, invasion host-tissues (eno), iron acquisition and uptake (piuA), the enzymes involved in the pathogenicity (cppA, htrA/degP, tig/ropA).In addition, cytolysin toxin encoded by cylA was detected in all 3 isolates.

| DISCUSSION
Streptococci are the second most common cause of infective endocarditis after staphylococci.The viridians streptococci, which comprise several species categorized into 5 groups, is responsible for about 30% of all streptococcal-related endocarditis. 15However, S. gordonii, which is a member of the S. sanguinis group, has rarely been reported to cause IE. 16 Intriguingly, significant numbers of cases of endocarditis caused by S. gordonii have been reported in one study; whether this is due to species differences in that specific geographical setting or a genuine increase prevalence of S. gordonii endocarditis requires more investigation. 16Usually, oral trauma, poor dental hygiene, mucositis, and recent dental procedures are risk factors for S. gordonii-associated endocarditis; however, they are rarely identified in the reported cases, as in our patients. 7,17. gordonii possesses several virulence factors facilitating the development of endocarditis.The ability to form biofilms, which is mediated by proteins PadA and Hsa, allows S. gordonii to efficiently bind to endothelial cells of heart valves and platelets, developing complex biofilms containing bacterium-platelet-fibrin complexes. 18nother potential virulence factor is a serine-rich glycoprotein, GspB, in the cell wall of S. gordonii, which leads to further platelet aggregation. 19Moreover, S. gordonii induces a nuclear factor-kappa B signaling pathway in the valve interstitial cells and the TLR2 signaling pathway through nitric oxide production, leading to excessive inflammatory conditions and further facilitating biofilm formation. 20,21For these reasons, antimicrobials might fail to penetrate this unique multilayer biofilm, leading to delaying source control. 8This particular ability of S. gordonii to form biofilms might explain why 2 out of 3 of our patients had large vegetations and valve complications that required surgery. 16Additionally, the formation of this distinct multilayer biofilm containing platelet aggregates might explain the increased rate of embolic events associated with S. gordonii IE 22 ; However, Chamat-Hedemand et al reported a low prevalence of embolization in patients with S. gordonii IE. 8 Noticeably, ischemic stroke, secondary to embolic events, is the presenting symptom in 20% of all streptococci endocarditis, F I G U R E 4 Phylogenetic tree analysis of the three S. gordonii isolates.as observed in the first case. 23Chamat-Hedemand et al, reported that the most common presenting symptoms for VGS-related IE were fever and heart murmur at 86% and 81%, respectively. 8They also found that, the aortic valve was infected in about half, the mitral valve in 36%, and both aortic and mitral valves in 17% of all VGS-related IE. 8 Despite all these characteristics, it is not possible to differentiate between IE caused by S. gordonii from that caused by other members of the VGS based on clinical, laboratory, and echocardiographic features.It is noteworthy that, when S. gordonii bacteremia is complicated by IE, it is more likely associated with multivalve involvement and younger age when compared with other VGSrelated IE. 16 Almost all our patients presented with fever and murmurs, with involvement of the mitral valves in two out of the three cases.
It is also worth noting that matrix-assisted laser desorption-ionization time-of-flight mass spectrometry (MALDI-TOF MS) has demonstrated to accurately identify viridans streptococci within the sanguinis group to the species level unlike the S. mitis group. 24The in-hospital mortality for VGS-related IE ranges from 10% to 29%, depending on patient characteristics and complications. 8he treatment of choice for highly penicillin-susceptible S. gordonii native valve endocarditis is a 4-week regimen of parenteral penicillin or ceftriaxone.Gentamicin should be added for the first 2 weeks of therapy if isolates with intermediate susceptibility to penicillin are detected. 9imely surgical intervention is crucial to improve prognosis and embolic events. 25nterestingly, novel therapeutic strategies that target major virulence factors, virulence-mediated pathways, and biofilm formation of S. gordonii could be a promising alternative or add-on to conventional antimicrobial therapy; however, further research is warranted to better understand the pathogenesis, molecular characteristics, and practicality of using these novel therapies. 26ur patients were young, had native heart valves, no history of dental disease, and presented during four-week period.Therefore, we used WGS to investigate this cluster of cases.
The small sample size limits the study generalizability and the accuracy of identifying single reference genome for SNPs when analyzing WGS data for epidemiological purposes, limiting standardization of the study.
We searched the PubMed, Embase, and Cochrane Library databases in November 2023 for similar cases.The search terms included "Streptococcus gordonii," "bacteremia," and "endocarditis,".We excluded infections caused by S. gordonii other than endocarditis.The search was restricted to articles written in English and yielded a total of 25 cases of S. gordonii -related endocarditis (Table 1 predominantly males.Four patients had recent dental procedures, 7,22,27,28 while only one reported a history of recently treated tonsillitis. 29Of all patients reviewed, only three had recent valve replacement/repair or abnormal valves as a risk factor for endocarditis. 7,30,31f the 25 cases reviewed, 64% reported a history of fever between 1 day and up to 24 weeks prior to presentation; however, in the remainder, the duration was not mentioned. 7,29itral valves were most commonly involved (52%), and in almost one-fifth of the cases, both the aortic and mitral valves were involved. 7,28,32][29][30][31][32] Septic emboli were reported in 36% (9 cases), of which 20% (5 cases) were settled in the brain, and 16% (4 cases) were evident in the spine, causing discitis. 7he duration of therapy ranged from 4 to 12 weeks, depending on the complication, although data were not always available.Only two deaths were identified in our review, 7,33 though 44% of the cases required valve surgery, either replacement or repair (Table 1).

| CONCLUSION
In summary, IE caused by S. gordonii is unusual and often associated with embolic events, and valve complications that require surgery, which is likely related to the unique ability of this species to attach and form biofilms along with the presence of distinct virulence factors.Therefore, timely recognition, early antimicrobial therapy, and a multidisciplinary approach involving infectious disease physicians, cardiologists, and cardiac surgeons are crucial to avoid valve destruction and detrimental consequences.

F
I G U R E 1 (A) TEE mid-esophageal view with large vegetation (*) on the anterior mitral leaflet with leaflet perforation (arrow).The posterior mitral leaflet (PML) is also affected with small vegetation (**).(B) Following treatment, there is a smaller residual vegetation (*) on the anterior mitral leaflet.The PML vegetation completely resolved.LA, Left atrium; LV, Left ventricle.U R E 2 TEE mid-esophageal views.Large, highly mobile vegetations (*) on both mitral leaflets with perforation of the posterior leaflet.

F I G U R E 3
The aortic valve is bicuspid.A 10 × 3 mm vegetation is seen (*) with possible nonruptured valvular abscess.Ao, Aorta; LV, Left ventricle.T A B L E 1 Summary of previously reported cases of S. gordonii endocarditis.